Pushing the boundaries of 3D-QSAR

Abstract

Based primarily on further studies of a collection of eleven publications reporting fifteen successful 3D-QSAR relations, several phenomena are preliminarily described. The RMS error of 133 ligand binding energy predictions based on these successful 3D-QSARs is 0.75 kcal/mole, which compares favorably to the prediction accuracies of approaches that include the receptor. A similar result is obtained when topomer alignments are substituted for those published, with seemingly profound implications for the future of 3D-QSAR. The “alignment-averaged” molecular properties, log P and molar refractivity, have very little correlative power for these data sets, either alone or in combination with the 3D-QSAR field descriptors. The q ² metric for the number of PLS components necessarily tends to discard any unique or unconfirmed SAR information. Large drops in q ² are thus to be expected whenever such unique information is first encountered. Predictive r ² values from an exploratory new “series trajectory” analysis of these 3D-QSAR though highly variable do not differ much from their q ² values, a phenomenon that seems to encourage prediction even when there are so few structures underlying a 3D-QSAR so that almost all information is unique.